Steroid Regulation of the GABAA Receptor: Ligand Binding, Chloride Transport and Behaviour

  1. Derek Chadwick Organizer and
  2. Kate Widdows
  1. Maria Dorota Majewska

Published Online: 28 SEP 2007

DOI: 10.1002/9780470513989.ch5

Ciba Foundation Symposium 153 - Steroids and Neuronal Activity

Ciba Foundation Symposium 153 - Steroids and Neuronal Activity

How to Cite

Majewska, M. D. (2007) Steroid Regulation of the GABAA Receptor: Ligand Binding, Chloride Transport and Behaviour, in Ciba Foundation Symposium 153 - Steroids and Neuronal Activity (eds D. Chadwick and K. Widdows), John Wiley & Sons, Ltd., Chichester, UK. doi: 10.1002/9780470513989.ch5

Author Information

  1. Addiction Research Center, National Institute on Drug Abuse, P.O. Box 5180, Baltimore, MD 21224, USA

Publication History

  1. Published Online: 28 SEP 2007

ISBN Information

Print ISBN: 9780471926894

Online ISBN: 9780470513989

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Keywords:

  • steroid regulation;
  • GABAA receptor complex;
  • ligand binding;
  • chloride transport;
  • chloride behavior

Summary

Certain endogenous steroids are modulators of GABAA receptors. Tetrahydroprogesterone (THP, 5α-pregnan-3α-ol-20-one) and tetrahydrodeoxy-corticosterone (THDOC, 5α-pregnane-3α,21-diol-20-one) behave as allosteric agonists of GABAA receptors whereas pregnenolone sulphate acts as an antagonist. THP and THDOC modulate ligand binding to GABAA receptors like barbiturates; they potentiate binding of the GABAA receptor agonist muscimol and the benzodiazepine flunitrazepam and they allosterically inhibit binding of the convulsant t-butylbicyclophosphorothionate. THP and THDOC also stimulate chloride uptake and currents in synaptoneurosomes and neurons. Pregnenolone sulphate acts principally as an allosteric GABAA receptor antagonist; it competitively inhibits binding of [35S]TBPS and blocks GABA agonist-activated Cl uptake and currents in synaptoneurosomes and neurons. In behavioural experiments the GABA-agonistic steroid THDOC shows anxiolytic actions whereas the GABA-antagonistic steroid pregnenolone sulphate antagonizes barbiturate-induced hypnosis. Changes in physiological levels of GABAergic steroids may alter GABAA receptor function, influencing neuronal excitability and CNS arousal. For example, pregnancy and the puerperium are associated with alterations in GABAA receptor binding which might be attributable to steroid actions.